The invention relates to a stent apparatus and to a method of treating hypoxia in vascular tissue, and to treatment and stenting methods of subjects with diabetes mellitus.
Blood vessel walls are comprised of living cells which are metabolically active and therefore require a supply of nutrients including oxygen. In the absence of disease, cells in blood vessel walls receive oxygen from the lumen via transmural diffusion of oxygen from the blood at the inside wall of the vessel. Capillary-like microscopic vessels that originate in the main vessel or another vessel and spread through the adventitia (outer layer) of the vessel, known as adventitial micro vessels, provide the outer portion of the vessel tissue with a supply of blood and consequently oxygen. Cells in tissue closer to the lumen wall of the vessel are more reliant on the transmural diffusion mechanism for their supply of oxygen.
Early fatty streak to advanced atherosclerotic lesions also contain inflammatory cells which exhibit a high level of metabolic activity requiring a continuous oxygen supply. Hypoxic conditions can emerge particularly at the intima-media transition due to the development of extra-cellular matrix in the intima as a result of previous inflammatory episodes in the vessel wall. In hypoxic conditions the metabolically active cells express hypoxia inducible factor (HIF) which triggers a defense mechanism which attempts to restore normoxic conditions and prevent hypoxia induced necrosis and loss of tissue integrity. A key component of this defence mechanism is angiogenesis.
Angiogenesis, which is the formation of new blood vessels, may be triggered by homeostatic imbalances including hypoxia. It may be classified as physiological angiogenesis in a normal state, being fundamental for development, reproduction and repair of blood vessels or pathological angiogenesis which is persistent due, for example, to the inability to restore normoxic conditions. Hypoxia is associated with inflammation and particularly an increased metabolic demand due to macrophage infiltration. Vessel wall hypoxia can be accentuated due to an accumulation of fatty streaks or extracellular matrix in the intima (the innermost lining of the vessel), which limits oxygen diffusion to the portion of the vessel wall exterior to the lesion. The resulting presence of HIF in the nuclei of macrophages triggers the upregulation of a number of angiogenic factors including vascular endothelial growth factor (VEGF) which initiates the development of new vessels which can improve the local oxygen supply and allow tissue repair. In physiological angiogenesis, after healing has taken place, the process is reversible and angiogenesis regresses. Therefore physiological angiogenesis occurs focally and is a self-limiting process.
However, pathological angiogenesis involves the persistence over a significant time period of angiogenic stimuli, including hypoxia. The persistent expression of VEGF results in immature neo-vessel formation with poorly formed microendothelium exhibiting incomplete gap junctions which leak red blood cells into the surrounding tissue in a process termed intra-plaque haemorrhage. Red blood cells are rich in cholesterol so this haemorrhage leads to lipid core expansion and increased plaque burden. Plaques which exhibit intra-plaque haemorrhage exhibit rapid progression and are associated with an increased occurrence of clinical events, as discussed in the paper “Plaque neovascularization: defense mechanisms, betrayal, or a war in progress” by Moreno et al. 2012, Annals of the New York Academy of Sciences 1254 (2012) 7-17.
The above mechanisms suggest a central role for vessel wall hypoxia in the development and progression of occlusive vascular disease. Such plaques are commonly treated by endovascular interventions including the placement of a stent to expand the vessel at the site of the blockage and maintain patency.